4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds

ABSTRACT

The present invention relates to novel 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production to Tumor necrosis Factor (TNF).

This application is a 371 of PCT/US96/08080 filed May 30, 1996 and acontinuation of U.S. Ser. No. 8/455,866 filed May 31, 1995 nowabandoned.

FIELD OF INVENTION

The present invention relates to novel4.4-(disubstituted)cyclohexan-1-ols monomers and related compounds,pharmaceutical compositions containing these compounds, and their use intreating allergic and inflammatory diseases and for inhibiting theproduction of Tumor Necrosis Factor (TNF).

BACKGROUND OF THE INVENTION

Bronchial asthma is a complex, multifactorial disease characterized byreversible narrowing of the airway and hyperreactivity of therespiratory tract to external stimuli.

Identification of novel therapeutic agents for asthma is made difficultby the fact that multiple mediators are responsible for the developmentof the disease. Thus, it seems unlikely that eliminating the effects ofa single mediator will have a substantial effect on all three componentsof chronic asthma. An alternative to the "mediator approach" is toregulate the activity of the cells responsible for the pathophysiologyof the disease.

One such way is by elevating levels of cAMP (adenosine cyclic3',5'-monophosphate). Cyclic AMP has been shown to be a second messengermediating the biologic responses to a wide range of hormones,neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4thInternational Congress Excerpta Medica, 17-29, 1973]. When theappropriate agonist binds to specific cell surface receptors, adenylatecyclase is activated, which converts Mg⁺² -ATP to cAMP at an acceleratedrate.

Cyclic AMP modulates the activity of most, if not all, of the cells thatcontribute to the pathophysiology of extrinsic (allergic) asthma. Assuch, an elevation of cAMP would produce beneficial effectsincluding: 1) airway smooth muscle relaxation, 2) inhibition of mastcell mediator release, 3) suppression of neutrophil degranulation, 4)inhibition of basophil degranulation, and 5) inhibition of monocyte andmacrophage activation. Hence, compounds that activate adenylate cyclaseor inhibit phosphodiesterase should be effective in suppressing theinappropriate activation of airway smooth muscle and a wide variety ofinflammatory cells. The principal cellular mechanism for theinactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by oneor more of a family of isozymes referred to as cyclic nucleotidephosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotidephosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMPbreakdown in airway smooth muscle and inflammatory cells. [Torphy,"Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmaticAgents" in New Drugs for Asthma, Barnes, ed. IBC Technical ServicesLtd., 1989]. Research indicates that inhibition of this enzyme not onlyproduces airway smooth muscle relaxation, but also suppressesdegranulation of mast cells, basophils and neutrophils along withinhibiting the activation of monocytes and neutrophils. Moreover, thebeneficial effects of PDE IV inhibitors are markedly potentiated whenadenylate cyclase activity of target cells is elevated by appropriatehormones or autocoids, as would be the case in vivo. Thus PDE IVinhibitors would be effective in the asthmatic lung, where levels ofprostaglandin E₂ and prostacyclin (activators of adenylate cyclase) areelevated. Such compounds would offer a unique approach toward thepharmacotherapy of bronchial asthma and possess significant therapeuticadvantages over agents currently on the market.

The compounds of this invention also inhibit the production of TumorNecrosis Factor (TNF), a serum glycoprotein. Excessive or unregulatedTNF production has been implicated in mediating or exacerbating a numberof diseases including rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions; sepsis,septic shock, endotoxic shock, gram negative sepsis, toxic shocksyndrome, adult respiratory distress syndrome, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, boneresorption diseases, reperfusion injury, graft vs. host reaction,allograft rejections, fever and myalgias due to infection, such asinfluenza, cachexia secondary to infection or malignancy, cachexiasecondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC(AIDS related complex), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis, or pyresis, in addition to a number ofautoimmune diseases, such as multiple sclerosis, autoimmune diabetes andsystemic lupus erythematosis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIVhave been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence ofHIV infection, T-cell-mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Viruses such as HIV-1 or HIV-2 infect T lymphocytes after Tcell activation and such virus protein expression and/or replication ismediated or maintained by such T cell activation. Once an activated Tlymphocyte is infected with HIV, the T lymphocyte must continue to bemaintained in an activated state to permit HIV gene expression and/orHIV replication.

Cytokines, specifically TNF, are implicated in activated T-cell-mediatedHIV protein expression and/or virus replication by playing a role inmaintaining T lymphocyte activation. Therefore, interference withcytokine activity such as by inhibition of cytokine production, notablyTNF, in an HIV-infected individual aids in limiting the maintenance of Tcell activation, thereby reducing the progression of HIV infectivity topreviously uninfected cells which results in a slowing or elimination ofthe progression of immune dysfunction caused by HIV infection.Monocytes, macrophages, and related cells, such as kupffer and glialcells, have also been implicated in maintenance of the HIV infection.These cells, like T cells, are targets for viral replication and thelevel of viral replication is dependent upon the activation state of thecells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection,Advances in Immunology, Vol. 57, 1989]. Monokines, such as TNF, havebeen shown to activate HIV replication in monocytes and/or macrophages[See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore,inhibition of monokine production or activity aids in limiting HIVprogression as stated above for T cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalovirus (CMV), influenza virus,adenovirus, and the herpes virus for similar reasons as those noted.

TNF is also associated with yeast and fungal infections. SpecificallyCandida albicans has been shown to induce TNF production in vitro inhuman monocytes and natural killer cells. [See Riipi et al., Infectionand Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal ofInfectious Diseases, 164:389-95, 1991. See also Wasan et al.,Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Lukeet al., Journal of Infectious Diseases, 162:211-214,1990].

The ability to control the adverse effects of TNF is furthered by theuse of the compounds which inhibit TNF in mammals who are in need ofsuch use. There remains a need for compounds which are useful intreating TNF-mediated disease states which are exacerbated or caused bythe excessive and/or unregulated production of TNF.

SUMMARY OF THE INVENTION

Compounds of the Formula (I): ##STR1## wherein: R₁ is --(CR₄ R₅)_(n)C(O)O(CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) C(O)NR₄ (CR₄ R₅)_(m) R₆, --(CR₄R₅)_(n) O(CR₄ R₅)_(m) R₆, or --(CR₄ R₅)_(r) R₆ wherein the alkylmoieties unsubstituted or substituted with one or more halogens;

m is 0 to 2;

n is 1 to 4;

r is 0 to 6;

R₄ and R₅ are independently selected hydrogen or C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl,aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl, indanyl, indenyl,C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl,C₃₋₆ cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted orsubstituted by 1 to 3 methyl groups, one ethyl group, or an hydroxylgroup;

provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ is hydroxyl, then r is 2 to 6; or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl,or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and m is 0, then R₆ is other than H in --(CR₄ R₅)_(n)O(CR₄ R₅)_(m) R₆ ;

X is YR₂, fluorine, NR₄ R₅, or formyl amine;

Y is O or S(O)_(m') ;

m' is 0, 1, or 2;

X₂ is O or NR₈ ;

X₃ is hydrogen or X;

X₄ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈ R₈, or NR₈ R₈ ;

R₂ is independently selected from --CH₃ or --CH₂ CH₃ optionallysubstituted by 1 or more halogens;

s is 0 to 4;

W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynylof 2 to 6 carbon atoms;

R₃ is COOR₁₄, C(O)NR₄ R₁₄ or R₇ ;

Z is OR₁₄, OR₁₅, SR₁₄, S(O)_(m') R₇, S(O)₂ NR₁₀ R₁₄, NR₁₀ R₁₄, NR₁₄C(O)R₉, NR₁₀ C(Y')R₁₄, NR₁₀ C(O)OR₇, NR₁₀ C(Y')NR₁₀ R₁₄, NR₁₀ S(O)₂ NR₁₀R₁₄, NR₁₀ C(NCN)NR₁₀ R₁₄, NR₁₀ S(O)₂ R₇, NR₁₀ C(CR₄ NO₂)NR₁₀ R₁₄, NR₁₀C(NCN)SR₉, NR₁₀ C(CR₄ NO₂)SR₉, NR₁₀ C(NR₁₀)NR₁₀ R₁₄, NR₁₀ C(O)C(O)NR₁₀R₁₄, or NR₁₀ C(O)C(O)OR₁₄ ;

Y' is O or S;

R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkylgroup is unsubstituted or substituted one or more times by methyl orethyl unsubstituted or substituted by 1-3 fluorines, --F, --Br, --Cl,--NO₂, --NR₁₀ R₁₁, --C(O)R₈, --CO₂ R₈, --O(CH₂)₂₋₄ OR₈, --O(CH₂)_(q) R₈,--CN, --C(O)NR₁₀ R₁₁, --O(CH₂)_(q) C(O)NR₁₀ R₁₁, --O(CH₂)_(q) C(O)R₉,--NR₁₀ C(O)NR₁₀ R₁₁, --NR₁₀ C(O)R₁₁, --NR₁₀ C(O)OR₉, --NR₁₀ C(O)R₁₃,--C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀ R₁₁, --C(NCN)SR₉, --NR₁₀ C(NCN)SR₉,--NR₁₀ C(NCN)NR₁₀ R₁₁, --NR₁₀ S(O)₂ R₉, --S(O)_(m) R₉, --NR₁₀C(O)C(O)NR₁₀ R₁₁, --NR₁₀ C(O)C(O)R₁₀, or R₁₃ ;

q is 0, 1, or 2;

R₁₂ is R₁₃, C₃ -C₇ cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl,pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl,morpholinyl, furanyl, (2- or 3-thienyl), uinolinyl, naphthyl, or phenyl;

R₈ is independently selected from hydrogen or R₉ ;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁ ;

R₁₁ is hydrogen, or C₁₋₄ alkyl unsubstituted or substituted by one tothree fluorines; or when R₁₀ and R₁₁ are as NR₁₀ R₁₁ they may togetherwith the nitrogen form a 5 to 7 membered ring comprised of carbon orcarbon and one or more additional heteroatoms selected from O, N, or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups unsubstituted or substitutedon the methyl with 1 to 3 fluoro atoms;

R₁₄ is hydrogen or R₇ ; or when R₈ and R₁₄ are as NR₈ R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring comprised ofcarbon or carbon and one or more additional heteroatoms selected from O,N, or S;

provided that:

(f) R₇ is not C₁₋₄ alkyl unsubstituted or substituted by one to threefluorines;

or the pharmaceutically acceptable salts thereof.

This invention also relates to the pharmaceutical compositionscomprising a compound of Formula (I) and a pharmaceutically acceptablecarrier or diluent.

The invention also relates to a method of mediation or inhibition of theenzymatic activity (or catalytic activity) of PDE IV in mammals,including humans, which comprises administering to a mammal in needthereof an effective amount of a compound of Formula (I) as shown below.

The invention further provides a method for the treatment of allergicand inflammatory disease which comprises administering to a mammal,including humans, in need thereof, an effective amount of a compound ofFormula (I).

The invention also provides a method for the treatment of asthma whichcomprises administering to a mammal, including humans, in need thereof,an effective amount of a compound of Formula (I).

This invention also relates to a method of inhibiting TNF production ina mammal, including humans, which method comprises administering to amammal in need of such treatment, an effective TNF inhibiting amount ofa compound of Formula (I). This method may be used for the prophylactictreatment or prevention of certain TNF mediated disease states amenablethereto.

This invention also relates to a method of treating a human afflictedwith a human immunodeficiency virus (HIV), which comprises administeringto such human an effective TNF inhibiting amount of a compound ofFormula (I).

Compounds of Formula (I) are also useful in the treatment of additionalviral infections, where such viruses are sensitive to upregulation byTNF or will elicit TNF production in vivo.

In addition, compounds of Formula (I) are also useful in treating yeastand fungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo.

DETAILED DESCRIPTION OF THE INVENTION

This invention also relates to a method of mediating or inhibiting theenzymatic activity (or catalytic activity) of PDE IV in a mammal in needthereof and to inhibiting the production of TNF in a mammal in needthereof, which comprises administering to said mammal an effectiveamount of a compound of Formula (I).

Phosphodiesterase IV inhibitors are useful in the treatment of a varietyof allergic and inflammatory diseases including: asthma, chronicbronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergicconjunctivitis, vernal conjunctivitis, eosinophilic granuloma,psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis,Crohn's disease, reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock and adult respiratory distresssyndrome. In addition, PDE IV inhibitors are useful in the treatment ofdiabetes insipidus and central nervous system disorders such asdepression and multi-infarct dementia.

The viruses contemplated for treatment herein are those that produce TNFas a result of infection, or those which are sensitive to inhibition,such as by decreased replication, directly or indirectly, by the TNFinhibitors of Formula (I). Such viruses include, but are not limited toHIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus andthe Herpes group of viruses, such as, but not limited to, Herpes zosterand Herpes simplex.

This invention more specifically relates to a method of treating amammal, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to such mammal an effective TNF inhibitingamount of a compound of Formula (I).

The compounds of this invention may also be used in association with theveterinary treatment of animals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to feline immunodeficiencyvirus (FIV) or other retroviral infection such as equine infectiousanemia virus, caprine arthritis virus, visna virus, maedi virus andother lentiviruses.

The compounds of this invention are also useful in treating yeast andfungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo. A preferreddisease state for treatment is fungal meningitis. Additionally, thecompounds of Formula (I) may be administered in conjunction with otherdrugs of choice for systemic yeast and fungal infections. Drugs ofchoice for fungal infections, include but are not limited to the classof compounds called the polymixins, such as Polymycin B, the class ofcompounds called the imidazoles, such as clotrimazole, econazole,miconazole, and ketoconazole; the class of compounds called thetriazoles, such as fluconazole, and itranazole, and the class ofcompound called the Amphotericins, in particular Amphotericin B andliposomal Amphotericin B.

The compounds of Formula (I) may also be used for inhibiting and/orreducing the toxicity of an anti-fungal, anti-bacterial or anti-viralagent by administering an effective amount of a compound of Formula (I)to a mammal in need of such treatment. Preferably, a compound of Formula(I) is administered for inhibiting or reducing the toxicity of theAmphotericin class of compounds, in particular Amphotericin B.

The term "C₁₋₃ alkyl", "C₁₋₄ alkyl", "₁₋₆ alkyl" or "alkyl" groups asused herein is meant to include both straight or branched chain radicalsof 1 to 10, unless the chain length is limited thereto, including, butnot limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, and the like.

"Alkenyl" means both straight or branched chain radicals of 1 to 6carbon lengths, unless the chain length is limited thereto, includingbut not limited to vinyl, 1-propenyl, 2-propenyl, 2-propynyl, or3-methyl-2-propenyl.

The term "cycloalkyl" or "cycloalkyl alkyl" means groups of 3-7 carbonatoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, orcyclohexyl.

"Aryl" or "aralkyl", unless specified otherwise, means an aromatic ringor ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl,or naphthyl. Preferably the aryl is monocyclic, i.e, phenyl. The alkylchain is meant to include both straight or branched chain radicals of 1to 4 carbon atoms.

"Heteroaryl" means an aromatic ring system containing one or moreheteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl,pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl.

"Halo" means all halogens, i.e., chloro, fluoro, bromo, or iodo.

"Inhibiting the production of IL-1" or "inhibiting the production ofTNF" means:

a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, ina human to normal levels or below normal levels by inhibition of the invivo release of IL-1 by all cells, including but not limited tomonocytes or macrophages;

b) a down regulation, at the translational or transcriptional level, ofexcessive in vivo IL-1 or TNF levels, respectively, in a human to normallevels or below normal levels; or

c) a down regulation, by inhibition of the direct synthesis of IL-1 orTNF levels as a postranslational event.

The phrase "TNF mediated disease or disease states" means any and alldisease states in which TNF plays a role, either by production of TNFitself, or by TNF causing another cytokine to be released, such as butnot limited to IL-1 or IL-6. A disease state in which IL-1, for instanceis a major component, and whose production or action, is exacerbated orsecreted in response to TNF, would therefore be considered a diseasestate mediated by TNF. As TNF-β (also known as lymphotoxin) has closestructural homology with TNF-α (also known as cachectin), and since eachinduces similar biologic responses and binds to the same cellularreceptor, both TNF-α and TNF-β are inhibited by the compounds of thepresent invention and thus are herein referred to collectively as "TNF"unless specifically delineated otherwise. Preferably TNF-α is inhibited.

"Cytokine" means any secreted polypeptide that affects the functions ofcells, and is a molecule which modulates interactions between cells inimmune, inflammatory, or hematopoietic responses. A cytokine includes,but is not limited to, monokines and lymphokines regardless of whichcells produce them.

The cytokine inhibited by the present invention for use in the treatmentof a HIV-infected human must be a cytokine which is implicated in (a)the initiation and/or maintenance of T cell activation and/or activatedT cell-mediated HIV gene expression and/or replication, and/or (b) anycytokine-mediated disease associated problem such as cachexia or muscledegeneration. Preferrably, his cytokine is TNF-α.

All of the compounds of Formula (I) are useful in the method ofinhibiting the production of TNF, preferably by macrophages, monocytesor macrophages and monocytes, in a mammal, including humans, in needthereof. All of the compounds of Formula (I) are useful in the method ofinhibiting or mediating the enzymatic or catalytic activity of PDE IVand in treatment of disease states mediated thereby.

Pharmaceutically acceptable salts of the instant compounds, where theycan be prepared, are also intended to be covered by this invention.These salts will be ones which are acceptable in their application to apharmaceutical use. By that it is meant that the salt will retain thebiological activity of the parent compound and the salt will not haveuntoward or deleterious effects in its application and use in treatingdiseases.

Preferred compounds are as follows:

When R₁ is an alkyl substituted by 1 or more halogens, the halogens arepreferably fluorine and chlorine, more preferably a C₁₋₄ alkylsubstituted by 1 or more fluorines. The preferred halo-substituted alkylchain length is one or two carbons, and most preferred are the moieties--CF₃, --CH₂ F, --CHF₂, --CF₂ CHF₂, --CH₂ CF₃, and --CH₂ CHF₂. PreferredR₁ substitutents for the compounds of Formula (I) are CH₂ -cyclopropyl,CH₂ --C₅₋₆ cycloalkyl, C₄₋₆ cycloalkyl unsubstituted or substituted withOHC₇₋₁₁ polycycloalkyl, (3- or 4-cyclopentenyl), phenyl,tetrahydrofuran-3-yl, benzyl or C₁₋₂ alkyl unsubstituted or substitutedby 1 or more fluorines, --(CH₂)₁₋₃ C(O)O(CH₂)₀₋₂ CH₃, --(CH₂)₁₋₃O(CH₂)₀₋₂ CH₃, and

When R₁ term contains the moiety (CR₄ R₅), the R₄ and R₅ terms areindependently hydrogen or alkyl. This allows for branching of theindividual methylene units as (CR₄ R₅)_(n) or (CR₄ R₅)_(m) ; eachrepeating methylene unit is independent of the other, e.g., (CR₄ R₅)_(n)wherein n is 2 can be --CH₂ CH(--CH₃)--, for instance. The individualhydrogen atoms of the repeating methylene unit or the branchinghydrocarbon can unsubstituted or be substituted by fluorine independentof each other to yield, for instance, the preferred R₁ substitutions, asnoted above.

When R₁ is a C₇₋₁₁ polycycloalkyl, examples are bicyclo[2.2.1]-heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0²,6 ]decyl,etc. additional examples of which are described in Saccamano et al., WO87/06576, published Nov. 5, 1987.

W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, andwhere it is alkenyl or alkynyl, that one or two double or triple bondsbe present. It is most preferred that W is acetylene or 1,3-butadiynyl.

Z is preferably OR₁₄, OR₁₅, SR₁₄, S(O)_(m') R₇, S(O)₂ NR₁₀ R₁₄, NR₁₀R₁₄, NR₁₄ C(O)R₉, NR₁₀ C(O)R₁₄, NR₁₀ C(O)OR₇, NR₁₀ C(O)NR₁₀ R₁₄, NR₁₀S(O)₂ NR₁₀ R₁₄, NR₁₀ C(NCN)NR₁₀ R₁₄, NR₁₀ S(O)₂ R₇, NR₁₀ C(CR₄ NO₂)NR₁₀R₁₄, NR₁₀ C(NCN)SR₉, NR₁₀ C(CR₄ NO₂)SR₉, NR₁₀ C(NR₁₀)NR₁₀ R₁₄, NR₁₀C(O)C(O)NR₁₀ R₁₄, or NR₁₀ C(O)C(O)OR₁₄.

Preferred X groups for Formula (I) are those wherein X is YR₂ and Y isoxygen. The preferred X₂ group for Formula (I) is that wherein X₂ isoxygen. The preferred X₃ group for Formula (I) is that wherein X₃ ishydrogen. Preferred R₂ groups, where applicable, is a C₁₋₂ alkylunsubstituted or substituted by 1 or more halogens. The halogen atomsare preferably fluorine and chlorine, more preferably fluorine. Morepreferred R₂ groups are those wherein R₂ is methyl, or thefluoro-substituted alkyls, specifically a C₁₋₂ alkyl, such as a --CF₃,--CHF₂, or --CH₂ CHF₂ moiety. Most preferred are the --CHF₂ and --CH₃moieties.

Preferred R₇ moieties include unsubstituted or substituted --(CH₂)₁₋₂(cyclopropyl), --(CH₂)₀₋₂ (cyclobutyl), --(CH₂)₀₋₂ (cyclopentyl)unsubstituted or substituted by OH, --(CH₂)₀₋₂ (cyclohexyl), --(CH₂)₀₋₂(2-, 3- or 4-pyridyl), (CH₂)₁₋₂ (2-imidazolyl), (CH₂)₂ (4-morpholinyl),(CH₂)₂ (4-piperazinyl), (CH₂)₁₋₂ (2-thienyl), (CH₂)₁₋₂ (4-thiazolyl),and (CH₂)₀₋₂ phenyl.

Preferred rings when R₁₀ and R₁₁ in the moiety --NR₁₀ R₁₁ together withthe nitrogen to which they are attached form a 5 to 7 membered ringcomprised of carbon or carbon and at least one heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl,2-(R₈)-1-imidazolyl, 1-pyrazolyl, 3-(R₈)-1-pyrazolyl, 1-triazolyl,2-triazolyl, 5-(R₈)-1-triazolyl, 5-(R₈)-2-triazolyl,5-(R₈)-1-tetrazolyl, 5-(R₈)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl,morpholinyl, piperazinyl, 4-(R₈)-1-piperazinyl, or pyrrolyl ring.

Preferred rings when R₁₀ and R₁₄ in the moiety --NR₁₀ R₁₄ together withthe nitrogen to which they are attached may form a 5 to 7 membered ringcomprised of carbon or carbon and at least one heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl,1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl,piperazinyl, and pyrrolyl. The respective rings may be additionallysubstituted, where applicable, on an available nitrogen or carbon by themoiety R₇ as described herein for Formula (I). Illustrations of suchcarbon substitutions includes, but is not limited to,2-(R₇)-1-imidazolyl, 4-(R₇)-1-imidazolyl, 5-(R₇)-1-imidazolyl,3-(R₇)-1-pyrazolyl, 4-(R₇)-1-pyrazolyl, 5-(R₇)-1-pyrazoyl,4-(R₇)-2-triazolyl, 5-(R₇)-2-triazolyl, 4-(R₇)-1-triazolyl,5-(R₇)-1-triazolyl, 5-(R₇)-1-tetrazolyl, and 5-(R₇)-2-tetrazolyl.Applicable nitrogen substitution by R₇ includes, but is not limited to,1-(R₇)-2-tetrazolyl, 2-(R₇)-1-tetrazolyl, 4-(R₇)-1-piperazinyl. Whereapplicable, the ring may be substituted one or more times by R₇.

Preferred groups for NR₁₀ R₁₄ which contain a heterocyclic ring are5-(R₁₄)-1-tetrazolyl, 2-(R₁₄)-1-imidazolyl, 5-(R₁₄)-2-tetrazolyl,4-(R₁₄)-1-piperazinyl, or 4-(R₁₅)-1-piperazinyl.

Preferred rings for R₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]),(5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]),(2-, 4-, or 5-thiazolyl), (2-, 4- or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

When the R₇ group is unsubstituted or substituted by a heterocyclic ringsuch as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, theheterocyclic ring itself may be unsubstituted or substituted by R₈either on an available nitrogen or carbon atom, such as1-(R₈)-2-imidazolyl, 1-(R₈)-4-imidazolyl, 1-(R₈)-5-imidazolyl,1-(R₈)-3-pyrazolyl, 1-(R₈)-4-pyrazolyl, 1-(R₈)-5-pyrazolyl,1-(R₈)-4-triazolyl, 1-(R₈)-5-triazolyl. Where applicable, the ring maybe substituted one or more times by R₈.

Preferred are those compounds of Formula (I) wherein R₁ is --CH₂-cyclopropyl, --CH₂ --C₅₋₆ cycloalkyl, --C₄₋₆ cycloalkyl unsubstitutedor substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl),benzyl or --C₁₋₂ alkyl unsubstituted or substituted by 1 or morefluorines, and --(CH₂)₂₋₄ OH; R₂ is methyl or fluoro-substituted alkyl,W is 1,3-butadiynyl; and X is YR₂.

Most preferred are those compounds wherein R₁ is --CH₂ -cyclopropyl,cyclopentyl, 3-hydroxycyclopentyl, methyl or CF₂ H; X is YR₂ ; Y isoxygen; X₂ is oxygen; X₃ is hydrogen; and R₂ is CF₂ H or methyl, W isacetylene or 1,3-butadiynyl, and R₃ is C(O)OR₁₄, or R₇.

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-trifluoromethyl[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-ol],

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-trifluoromethyl[1,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-1-ol],

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-trifluoromethyl[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-ol],and

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-trifluoromethyl[1,3,4]thiadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-ol].

It will be recognized that some of the compounds of Formula (I) mayexist in both racemic and optically active forms; some may also exist indistinct diastereomeric forms possessing distinct physical andbiological properties. All of these compounds are considered to bewithin the scope of the present invention.

Pharmaceutically acceptable salts are prepared in a standard manner. Theparent compound, dissolved in a suitable solvent, is treated with anexcess of an organic or inorganic acid, in the case of acid additionsalts of a base, or an excess of organic or inorganic base where themolecule contains a COOH for example.

Pharmaceutical compositions of the present invention comprise apharmaceutical carrier or diluent and some amount of a compound of theformula (I). The compound may be present in an amount to effect aphysiological response, or it may be present in a lesser amount suchthat the user will need to take two or more units of the composition toeffect the treatment intended. These compositions may be made up as asolid, liquid or in a gaseous form. Or one of these three forms may betransformed to another at the time of being administered such as when asolid is delivered by aerosol means, or when a liquid is delivered as aspray or aerosol.

The nature of the composition and the pharmaceutical carrier or diluentwill, of course, depend upon the intended route of administration, forexample parenterally, topically, orally or by inhalation.

For topical administration the pharmaceutical composition will be in theform of a cream, ointment, liniment, lotion, pastes, aerosols, and dropssuitable for administration to the skin, eye, ear, or nose.

For parenteral administration the pharmaceutical composition will be inthe form of a sterile injectable liquid such as an ampule or an aqueousor non-aqueous liquid suspension.

For oral administration the pharmaceutical composition will be in theform of a tablet, capsule, powder, pellet, atroche, lozenge, syrup,liquid, or emulsion.

When the pharmaceutical composition is employed in the form of asolution or suspension, examples of appropriate pharmaceutical carriersor diluents include: for aqueous systems, water; for non-aqueoussystems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil,peanut oil, sesame oil, liquid parafins and mixtures thereof with water;for solid systems, lactose, kaolin and mannitol; and for aerosolsystems, dichlorodifluoromethane, chlorotrifluoroethane and compressedcarbon dioxide. Also, in addition to the pharmaceutical carrier ordiluent, the instant compositions may include other ingredients such asstabilizers, antioxidants, preservatives, lubricants, suspending agents,viscosity modifiers and the like, provided that the additionalingredients do not have a detrimental effect on the therapeutic actionof the instant compositions.

The pharmaceutical preparations thus described are made following theconventional techniques of the pharmaceutical chemist as appropriate tothe desired end product.

In these compositions, the amount of carrier or diluent will vary butpreferably will be the major proportion of a suspension or solution ofthe active ingredient. When the diluent is a solid it may be present inlesser, equal or greater amounts than the solid active ingredient.

Usually a compound of formula I is administered to a subject in acomposition comprising a nontoxic amount sufficient to produce aninhibition of the symptoms of a disease in which leukotrienes are afactor. Topical formulations will contain between about 0.01 to 5.0% byweight of the active ingredient and will be applied as required as apreventative or curative agent to the affected area. When employed as anoral, or other ingested or injected regimen, the dosage of thecomposition is selected from the range of from 50 mg to 1000 mg ofactive ingredient for each administration. For convenience, equal doseswill be administered 1 to 5 times daily with the daily dosage regimenbeing selected from about 50 mg to about 5000 mg.

No unacceptable toxicological effects are expected when these compoundsare administered in accordance with the present invention.

Methods Of Preparation

Synthetic Scheme(s) With Textual Description

Compounds of Formula (I) may be prepared by the processes disclosedherein which comprise reacting a terminal acetylene, wherein Zrepresents Z as defined in relation to Formula (I) or a groupconvertible to Z, as, e.g., compound 1-Scheme 1, with an appropriatehalide, R₃ X, wherein R₃ represents R₃ as defined in relation to Formula(I) or a group convertible to R₃, in the presence of a suitablecatalyst, such as a copper (I) halide and a bivalent or zerovalentpalladium compound in the presence of, e.g., triphenylphosphine, in asuitable solvent, such as an amine, as in the procedure of Brandsma etal. (Syn. Comm., 1990, 20, 1889), provides a compound of the Formula2-Scheme 1. Compounds of the Formula 1-Scheme 1 may be prepared byprocedures analogous to those described in copending U.S. application07/862111, 07/968761 and PCT application number PCT/US93/02516 publishedunder WIPO publication number W093/19751. ##STR2##

Alternatively, compounds of the Formula (I), wherein Z and R₃ representZ and R₃ as defined in relation to Formula (I) or a group convertible toZ or R₃, may be prepared from the corresponding ketones as, e.g.,compound 1-Scheme 2, by the synthetic procedures described in PCTapplication number PCT/US93/01990 and PCT/US93/02325 published as WIPOpublication number WO93/19750. ##STR3##

Alternatively, oxidative carbonylation of a terminal acetylene as, e.g.,compound 1-Scheme 3, using an appropriate metal salt, such as a coppersalt with a catalytic amount of a palladium salt, in the presence of asuitable base as an acid trap, such as sodium acetate, in a suitablealcohol, such as methanol, as in the method of Tsuji et al. (Tet. Lett.,1980, 21, 849), then provides the compound of the Formula 2-Scheme 3;such compounds may then be converted to other compounds of the Formula(I) by manipulation of the ketone as described above and by independentmanipulation of the carboxylic ester moiety using standardtransesterification or amidation conditions. Syntheses of such ketonestarting materials are described in published PCT applicationPCT/US93/02045 (WIPO publication number WO 93/19748) or published PCTapplication PCT/US93/02325 (WIPO publication number WO/93/19750).##STR4##

Likewise, oxidative carbonylation of a terminal acetylene as, e.g.,compound 1-Scheme 4, wherein Z represents Z as defined in relation toFormula (I) or a group convertible to Z, using an appropriate metalsalt, such as a copper salt with a catalytic amount of a palladium salt,in the presence of a suitable base as an acid trap, such as sodiumacetate, in a suitable alcohol, such as methanol, as in the method ofTsuji et al. (Tet. Lett., 1980, 21, 849), then provides the compound ofthe Formula 2-Scheme 4; such compounds may then be converted to othercompounds of the Formula (I) by manipulation of the carboxylic estermoiety using standard transesterification or amidation conditions.##STR5##

Compounds where Z is a group other than --OH can be prepared by methodsknown in the art and in particular by manipulation of the --OH. Suchmethods are described in co-pending U.S. application 07/968753 and PCTapplication serial number PCT/US93/02325 (WIPO publication numberWO/93/19750).

Preparation of the remaining compounds of the Formula (I) may beaccomplished by procedures analogous to those described above and in theExamples, infra.

It will be recognized that some compounds of the Formula (I) may existin distinct diastereomeric forms possessing distinct physical andbiological properties; such isomers may be separated by standardchromatographic methods.

The following examples are given to further illustrate the describedinvention. These examples are intented solely for illustrating theinvention and should not be read to limit the invention in any manner.Reference is made to the claims for what is reserved to the inventorshereunder.

EXPERIMENTALS EXAMPLE 1 Preparation ofcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan-1-ol]

1 a)trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol]and cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol]

To a solution of4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.34 g,1.1 mmol, prepared as described in published PCT applicationPCT/US93/001990 (WIPO publication number WO 93/19748) or PCT/US93/02325(WIPO publication number WO/93/19750) in 1,2-dimethoxyethane (5 mL)under an argon atmosphere was added sodium borohydride (0.08 g, 2.2mmol) and the mixture was stirred at room temperature for 0.5 h. Waterwas added, the mixture was extracted three times with dichloromethane,was dried (magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 3:7 ethyl acetate:hexanes, providedtrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol](described in U.S. patent application in PCT application No.PCT/US93/02516 published under WIPO publication number WO93/19751₋₋ ascis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol]) asa wax. ¹ H-NMR (400 MHz, CDCl₃) δ 7.14 (d, J=2.3 Hz, 1H), 7.04 (dd,J=8.5, 2.3 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.79 (m, 1H), 3.83 (s, 3H),3.68 (m, 1H), 2.46 (s, 1H), 1.7-2.1 (m, 14H), 1.6 (m, 2H).

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] alsowas isolated from this procedure as a colorless oil. ¹ H-NMR (400 MHz,CDCl₃) δ 7.17 (d, J=1.9 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.4Hz, 1H), 4.80 (m, 1H), 4.13 (br s, 1H), 3.84 (s, 3H), 2.38 (s, 1H), 2.15(m, 4H), 1.7-2.0 (m, 10H), 1.75 (m, 2H).

1b)cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan-1-ol]

To a solution oftrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol](0.15 g, 0.48 mmol) and 4-bromopyridine (0.75 g, 5 mmol) in piperidine(2 mL) under an argon atmosphere were addedtetrakis(triphenylphosphine)palladium(0) (0.022 g, 4%), copper (I)iodide (0.005 g, 6%) and a small crystal of triphenylphosphine, and themixture was heated at 80-85° C. for 0.5 h. Ammonium chloride was addedand the mixture was extracted three times with dichloromethane, theextract was dried (magnesium sulfate) and was evaporated. Purificationby flash chromatography, eluting with 3:1 ethyl acetate/hexanes,providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)-cyclohexan-1-ol]as a pale yellow solid, which was triturated from ether-hexanes. mp183-184° C. ¹ H-NMR (400 MHz, CDCl₃) δ 8.6 (br, 2H), 7.35 (m, 2H), 7.14(d, J=2 Hz, 1H), 7.06 (dd, J=8.5, 2 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H),4.79 (m, 1H), 3.85 (s, 3H), 3.7 (m, 1H), 1.8-2.1 (m, 14H), 1.6 (m, 2H).

EXAMPLE 2cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexan-1-ol]

To a solution oftrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol](0.14 g, 0.43 mmol) and 2-bromopyridine (0.40 mL, 4.3 mmol) inpiperidine (2 mL) under an argon atmosphere were addedtetrakis(triphenyl-phosphine)palladium(0) (0.020 g, 4%), copper(I)iodide (0.005 g, 6%) and a small crystal of triphenylphosphine, and themixture was heated at 80-85° C. for 0.5 h. Ammonium chloride was addedand the mixture was extracted three times with dichloromethane, wasdried (magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 75:25 ethyl acetate:hexanes, providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexan-1-ol]as a white solid (0.14 g, 84%), mp 49-51° C. Anal. (C₂₅ H₂₉ NO₃.0.5 H₂O) calcd: C, 74.97; H, 7.55; N, 3.50; found: C, 74.90; H, 7.52; N, 3.33.

EXAMPLE 3 Resolution of(+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclohexan-1-one

The compound from Example lb was resolved in the following manner togive enantiomeric oils: HPLC R_(t) =15.5 min (enantiomer 1=E1), 23.2 min(enantiomer 2=E2) (Diacel Chiralpak AS; 21.2×250 mm; hexane:isopropanol,4:1; 10 mL/min; UV detection at 295 nm).

EXAMPLE 4 Preparation of (+/-)3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylcyclohexan-1-one

To a solution of the compound of Example 1b (0.125 g, 0.4 mmol) andiodobenzene (0.4 mL, 2.0 mmol) in piperidine (6 mL) under an argonatmosphere was added trace tetrakis(triphenylphosphine)palladium(0),copper(I) iodide and triphenylphosphine. The mixture was refluxed for 5h, then concentrated in vacuo. The residue was diluted with ethylacetate (100 mL), was washed with brine, was dried (MgSO₄) and wasevaporated. Purification by flash chromatography, eluting with 2:1hexanes/ethyl acetate, followed by trituration from ether/hexanes,provided the title compound as white solid (0.09 g, 58%), m.p. 90-91° C.

EXAMPLE 5 Preparation of (+/-)3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-carbomethoxyphenyl)ethynyl-cyclohexan-1-one

5a) methyl 3-iodobenzoate

Methyl 3-iodobenzoate was prepared by standard chemistry well known tothose versed in the art and is a white solid, m.p. 40-41° C.

5b) (+/-)3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-carbomethoxyphenyl)ethynyl-cyclohexan-1-one

To a solution of the compound from Example 1b (0.30 g, 0.96 mmol) andmethyl 3-iodobenzoate (0.30 g, 1.15 mmol) in triethylamine (10 mL) underan argon atmosphere was added tracetetrakis(triphenylphosphine)palladium(0), copper(I) iodide andtriphenylphosphine. The mixture was refluxed for 0.5 h and was thenconcentrated in vacuo. The residue was partitioned between water andethyl acetate. The organic phase was dried (Na₂ SO₄) and was evaporated.Purification by flash chromatography, eluting with 2:1 hexanes/ethylacetate, provided the title compound as a pale yellow oil (0.35 g, 80%).Anal (C₂₈ H₃₀ O₅.1.0 H₂ O) calcd: C, 72.39; H, 6.94; found: C, 72.47; H,6.80.

EXAMPLE 6 Preparation of (+/-)3-(3-carboxyphenylethynyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one

To a solution of the compound from Example 5(b) in 5:5:2THF/methanol/water (10 mL) under an argon atmosphere was added sodiumhydroxide (0.60 g, 1.5 mmol). The mixture was heated at 60° C. for 2 hand was then concentrated in vacuo. The residue was extracted from 3NHCl with ethyl acetate, was washed with brine, was dried (MgSO₄) and wasevaporated. Purification by flash chromatography, eluting with 98:2:0.3chloroform/methanol/acetic acid, provided a white solid, m.p. 71-73° C.

EXAMPLE 7 Preparation of3-(3-cyclopentyloxy-4-methoxyphenyl)-3[3-(5-methyl-[1,3,4]thiadiazol-2-yl)phenylethynyl]cyclohexan-1-one7a) 1-iodo-3-(5-methyl-[1,3,4]thiadiazol-2-yl)benzene

1-Iodo-3-(5-methyl-[1,3,4]thiadiazol-2-yl)benzene was prepared bystandard chemistry well known to those versed in the art and is whitesolid, m.p. 86-89° C.

7b)3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-methyl-[1,3,4]thiadiazol-2-yl)phenylethynyl]cyclohexan-1-one

To a solution of the compound from Example 3 (E1) (0.10 g, 0.32 mmol)and 1-iodo-3-(5-methyl-[1,3,4]thiadiazol-2-yl)benzene (0.10 g, 0.32mmol) in triethylamine (5 mL) under an argon atmosphere was added tracetetrakis(triphenylphosphine)palldium(0), copper(I) iodide andtriphenylphosphine. The mixture was refluxed for 0.20 h, was cooled toroom temperature and was concentrated in vacuo. The residue waspartitioned between ethyl acetate and water. The organic phase waswashed with brine, was dried (MgSO₄) and was evaporated. Purification byflash chromatography, eluting with 1:1 hexanes/ethyl acetate providedthe title compound as a white solid (0.135 g, 87%), m.p. 97-99° C.

The enantiomer was prepared in a similar manner, starting with thecompound from Example 3 (E2), as a white solid, m.p. 97-99° C.

EXAMPLE 8 Preparation of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)phenylethynyl]cyclohexan-1-one

8a) 1-iodo-3-(5-methyl-[1,3,4]oxadizol-2-yl)benzene

1-Iodo-3-(5-methyl-[1,3,4]oxadiazol-2-yl)benzene was prepared bystandard chemistry well known to those versed in the art and is a whitesolid, m.p. 104-105° C.

8b)3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)phenylethynyl]cyclohexan-1-one

To a solution of the compound from Example 3 (El) (0.125 g, 0.4 mmol)and 1-iodo-3-(5-methyl-[1,3,4]oxadiazol-2-yl)benzene (0.09 g, 0.32 mmol)in triethylamine (3 mL) under an argon atmosphere was added tracetetrakis(triphenylphosphine)palladium(0), copper(I) iodide andtriphenylphosphine. The mixture was heated at 80° C. for 0.2 h, wascooled to room temperature and was concentrated in vacuo. The residuewas partitioned between ethyl acetate and water. The organic phase waswashed with brine, was dried (MgSO₄) and was evaporated. Purification byflash chromatography, eluting with 2:1 ethyl acetate/hexanes, followedby recrystallization from ethyl acetate/hexanes, provided the titlecompound as a white solid (0.11 g, 61%), m.p. 117-119° C.

The enantiomer was prepared in a similar manner, starting with thecompound from Example 3 (E2), as a white solid, m.p. 117-119° C.

EXAMPLE 9 Preparation of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenylethynyl]cyclohexan-1-one

9a) 1-iodo-3-(3-methyl-[1,2,4]oxadiazol-5-yl)benzene

1-Iodo-3-(3-methyl-[1,2,4]oxadiazol-5-yl)benzene was prepared bystandard chemistry well known to those versed in the art and is a whitesolid, m.p. 101.5-103° C.

9b)3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenylethynyl]cyclohexan-1-one

To a solution of the compound from Example 3 (E1) (0.125 g, 0.4 mmol)and 1-iodo-3-(3-methyl-[1,2,4]oxadiazol-5-yl)benzene (0.09 g, 0.32 mmol)in triethylamine (3mL) under an argon atmosphere was added tracetetrakis(triphenylphosphine)palladium(0), copper(I) iodide andtriphenylphosphine. The mixture was heated at 80° C. for 0.2 h, wascooled to room temperature and was concentrated in vacuo. The residuewas partitioned between ethyl acetate and water. The organic phase waswashed with brine, was dried (MgSO₄) and was evaporated. The residue waspurified by flash chromatography, eluting with 2:1 hexanes/ethylacetate, followed by trituration from hexanes/ethyl acetate, to providethe title compound as a white solid, m.p. 122-123° C.

The enantiomer was prepared in a similar manner, starting with thecompound from Example 3 (E2), as awhite solid, m.p. 122-123° C.

EXAMPLE 10 Preparation of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylethynyl]cyclohexan-1-one

10a) 1-iodo-3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzene

1-iodo-3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzene was prepared bystandard chemistry well known to those versed in the art and is a whitesolid, m.p. 86-87° C.

10b)3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylethynyl]cyclohexan-1-one

To a solution of the compound from Example 3 (E1) (0.125 g, 0.4 mmol)and 1-iodo-3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzene (0.09 g, 0.32 mmol)in triethylamine (3 mL) under an argon atmosphere was added tracetetrakis(triphenylphosphine)palladium(0), copper(I) iodide andtriphenylphosphine. The mixture was heated at 80° C. for 0.2 h, wascooled to room temperature and was concentrated in vacuo. The residuewas partitioned between ethyl acetate and water. The organic phase waswashed with brine, was dried (MgSO₄) and was evaporated. Purification byflash chromatography, eluting with 2:1 hexanes/ethyl acetate, followedby trituration from hexanes/ethyl acetate, provided the title compoundas colorless crystals (0.12 g, 67%), m.p. 116-118° C.

The enantiomer was prepared in a similar manner, starting with thecompound from Example 3 (E2), as colorless crystals, m.p. 116-118° C.

EXAMPLE 11 Preparation of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-cyanophenylethynyl)cyclohexan-1-one

To a solution of the compound from Example 3 (E1) (0.125 g, 0.4 mmol)and 3-iodobenzonitrile (Transworld, 0.09 g, 0.4 mmol) in triethylamine(3 mL) under an argon atmosphere was added tracetetrakis(triphenylphosphine)palladium(0), copper(I) iodide andtriphenylphosphine. The mixture was heated at 80° C. for 0.2 h, wascooled to room temperature and was concentrated in vacuo. The residuewas partitioned between ethyl acetate and water. The organic phase waswashed with brine, was dried (MgSO₄) and was evaporated. The residue waspurified by flash chromatography, eluting with 2:1 hexanes/ethylacetate, to provide the title compound as a clear yellow glass (0.12 g,73%). MS(EI) m/e 414 [M+H]⁺.

The enantiomer was prepared in similar manner, starting with thecompound from Example 3 (E2), as a clear yellow glass.

EXAMPLE 12 Preparation of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-nitrophenylethynyl)cyclohexan-1-one

To a solution of the compound from Example 3 (E1) (0.2 g, 0.64 mmol) and3-iodonitrobenzene (Aldrich, 0.16 g, 0.64 mmol) in triethylamine (4 mL)under an argon atmosphere was added tracetetrakis(triphenylphosphine)palladium(0), copper(I) iodide andtriphenylphosphine. The mixture was heated at 80° C. for 0.2 h, wascooled to room temperature and was concentrated in vacuo. The residuewas partitioned between ethyl acetate and water. The organic phase waswashed with brine, was dried (MgSO₄) and was evaporated. Purification byflash chromatography, elutirg with 3:1 hexanes/ethyl acetate, providedthe title compound as yellow solid (0.25 g, 90%), m.p. 46-48° C.

The enantiomer was prepared in a similar manner, starting with thecompound from Example 3 (E2), as a yellow solid. m.p. 46-48° C.

EXAMPLE 13 Preparation of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(2-hydroxyethoxyphenylethynyl)cyclohexan-1-one

13a) 2-hydroxyethoxy-1-iodobenzene

2-hydroxyethoxy-1-iodobenzene was prepared by standard chemistry wellknown to those versed in the art and is a colorless oil. ¹ H NMR(400MHz, CDCl₃) δ 7.77 (dd, J=7.9, 1.3 Hz, 1H), 7.3 (t, J=7H, 1H), 6.84 (d,J=7.9 Hz, 1H), 6.74 (t, J=7.9 Hz, 1H), 4.13 (t, J=4.3 Hz, 2H), 3.99 (t,J=4.3 Hz, 2H), 2.2 (br s, 1H).

13b)3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(2-hydroxyethoxyphenylethynyl)cyclohexan-1-one

To a solution of the compound from Example 3 (E1) (0.25 g, 0.8 mmol) and2-hydroxyethoxy-1-iodobenzene (0.21 g, 0.8 mmol) in triethylamine (5 mL)under an argon atmosphere was added tracetetrakis(triphenylphosphine)palladium(0), copper(I) iodide andtriphenylphosphine. The mixture was heated at 80° C. for 1 h, was cooledto room temperature and was concentrated in vacuo. The residue waspartitioned between ethyl acetate and water. The organic phase waswashed with brine, was dried (MgSO₄) and was evaporated. Purification byflash chromatography, eluting with 1:1 hexanes/ethyl acetate, providedthe title compound as a white solid (0.05 g, 14%), m.p. 93-94° C.

EXAMPLE 14 Preparation of3-(3-acetamidophenylethynyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

14a) 3-acetamido-1-iodobenzene

3-acetamido-1-iodobenzene was prepared by standard chemistry well knownto those versed in the art and is a white solid, m.p. 117-118° C.

14b)3-(3-acetamidophenylethynyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one

To a solution of the compound from Example 3 (E1) (0.2 g, 0.64 mmol) and3-acetamido-1-iodobenzene (0.17 g, 0.64 mmol) in triethylamine (5 mL)under an argon atmosphere was added tracetetrakis(triphenylphosphine)palladium(0), copper(I) iodide andtriphenylphosphine. The mixture was heated at 80° C. for 0.3 h, wascooled to room temperature and was concentrated in vacuo. The residuewas purified by flash chromatography, eluting with 1:1 hexanes/ethylacetate, to provide the title compound as tan solid (0.17 g, 60%), m.p.58-60° C.

EXAMPLE 15 Preparation of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-methanesulfonamidophenylethynyl)cyclohexan-1-one

15a) 1-iodo-3-methanesulfonamidobenzene

1-iodo-3-methanesulfonamidobenzene was prepared by standard chemistrywell known to those versed in the art and is light-pink solid, m.p.102-103° C.

15b)3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-methanesulfonamidophenylethynyl)cyclohexan-1-one

To a solution of the compound from Example 3 (E1) (0.2 g, 0.64 mmol) and1-iodo-3-methanesulfonamidobenzene (0.19 g, 0.64 mmol) in triethylamine(5 mL) under an argon atmosphere was added tracetetrakis(triphenylphosphine)palladium(0), copper(I) iodide andtriphenylphosphine. The mixture was heated at 80° C. for 0.3 h, wascooled to room temperature and was concentrated in vacuo. The residuewas purified by flash chromatography, eluting with 1:1 hexanes/ethylacetate, to provide the title compound as a tan solid (0.18 g, 58%),m.p. 59-62° C.

EXAMPLE 16 Preparation of3-(3-aminophenylethynyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

16a) 1-iodo-3-trifluoroacetamidobenzene

1-iodo-3-trifluoroacetamidobenzene was prepared by standard chemistrywell known to those versed in the art and is a white solid, m.p.120-121° C.

16b)3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-trifluoroacetamidophenylethynyl)cyclohexan-1-one

To a solution of the compound from Example 3 (E1) (0.5 g. 1.6 mmol) and1-iodo-3-trifluoroacetamidobenzene (0.5 g, 1.6 mmol) in triethylamine(10 mL) under an argon atmosphere was added a small amount oftetrakis(triphenylphosphine)palladium(0), copper(I) iodide andtriphenylphosphine. The mixture was heated at 80° C. for 0.2 h, wascooled to room temperature and was concentrated in vacuo. The residuewas purified by flash chromatography, eluting with 3:1 hexanes/ethylacetate, to give the title compound as a pale yellow solid (0.62 g,78%), m.p. 63-65° C.

16c)3-(3-aminophenylethynyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

To a solution of3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-trifluoroacetamidophenylethynyl)cyclohexan-1-one(0.62 g, 1.24 mmol) in 95:5 methanol/water (10 mL) under an argonatmosphere was added potassium carbonate (0.86 g, 6.2 mmol). The mixturewas refluxed for 6 h and was stirred for 18 h at room temperature. Thesolid precipitate was collected and purified by trituration from ethylacetate/hexanes to provide the title compound as a white solid (0.39 g,77%), m.p. 100-102° C.

EXAMPLE 17cis-[4-(4-cyanothien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol]17a)2-bromo-4-cyanothiophene

2-Bromo-5-cyanothiophene was prepared by standard chemistry well knownto those versed in the art and is a colorless oil. ¹ H-NMR (400 MHz,CDCl₃) δ 7.85 (d, J=2.2 Hz, 1H), 7.25 (d, J=2.2 Hz, 1H) ppm.

17b)cis-[4-(4-cyanothien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol]

To a solution oftrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol](0.20 g, 0.64 mmol) and 2-bromo-4-cyanothiophene (0.12 g, 0.64 mmol) intriethylamine (5 mL) under an argon atmosphere were addedtetrakis(triphenyl-phosphine)palladium(0) (0.030 g, 4%), copper(I)iodide (0.008 g, 6%), and a small crystal of triphenylphosphine, and themixture was heated at 80-85° C. for 0.5 h. Hydrochloric acid (5%) wasadded and the mixture was extracted three times with dichloromethane,was dried (magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 1:1 ethyl acetate:hexanes, followed bytrituration from dichloromethane-hexanes, providedcis-[4-(4-cyanothien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol]as a pale yellow solid (0.12 g, 45%), mp 70-71° C. Anal. (C₂₅ H₂₇ NO₃ S)calcd: C, 71.23; H, 6.46; N, 3.30; found: C, 71.24; H, 6.72; N, 3.14.

EXAMPLE 18cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-ol]

18a) 2-bromo-4-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene

2-Bromo-4-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene was prepared bystandard chemistry well known to those versed in the art and is a whitesolid, mp 72-73° C.

18b)cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-ol]

To a solution oftrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol](0.25 g, 0.8 mmol) and2-bromo-4-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene (0.20 g, 0.8 mmol)in triethylamine (5 mL) under an argon atmosphere were addedtetrakis(triphenylphosphine)palladium(0) (0.038 g, 4%), copper(I) iodide(0.009 g, 6%) and a small crystal of triphenylphosphine, and the mixturewas heated at 70-75° C. for 0.5 h. Hydrochloric acid (5%) was added andthe mixture was extracted three times with dichloromethane, was dried(magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 1:1 ethyl acetate:hexanes, provided cis[4-(3-cyclopentyloxy-4-methoxyphenyl)4-[4-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-ol],which was further triturated from dichloromethane-hexanes to give awhite solid (0.20 g, 53%), mp 142-143° C. Anal. (C₂₇ H₃₀ N₂ O₄ S.0.75 H₂O) calcd: C, 65.90; H, 6.45; N, 5.69; found: C, 66.06; H, 6.42; N, 5.50.

EXAMPLE 19cis-[4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-ol]

19a) 4-iodo-2-thiomethylpyrimidine

4-Iodo-2-thiomethylpyrimidine was prepared following literatureprocedure (A. J. Majeed, .O slashed.. Antonsen, T. Benneche, K. Undheim.Tetrahedron 1989, 45, 993-1006).

19b)cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylthiopyrimidin-4-ylethynyl)cyclohexan-1-ol]

To a solution oftrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol](0.30 g, 0.95 mmol) and and 4-iodo-2-thiomethylpyrimidine (0.50 g, 2.5mmol, as a mixture of 4-iodo-2-thiomethylpyrimidine and4-chloro-2-thiomethylpyrimidine) in triethylamine (2 mL) under an argonatmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.044 g,4%) and copper(I) iodide (0.010 g, 6%), and the mixture was heated at80-85° C. for 0.5 h. Ammonium chloride was added and the mixture wasextracted three times with dichloromethane, was dried (magnesiumsulfate) and was evaporated. Purification by flash chromatography,eluting with 1:1 ethyl acetate:hexanes, providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylthiopyrimidin-4-ylethynyl)cyclohexan-1-ol]as a yellow oil (0.36 g, 87%). ¹ H-NMR (400 MHz, CDCl₃) δ 8.45 (d, J=5.0Hz, 1H), 7.15 (d, J=2.3 Hz, 1 H), 7.03 (dd, J=8.5, 2.3 Hz, 1H), 7.01 (d,J=5.0 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.81 (m, 1H), 3.84 (s, 3 H), 3.72(m, 1 H), 2.57 (s, 3 H), 2.14 (br d, J=12 Hz, 2 H), 2.05 (m, 2 H),1.8-2.0 (m, 10 H), 1.6 (m, 2 H) ppm.

19c)cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylsulfonylpyrimidin-4-ylethynyl)cyclohexan-1-ol]

To a solution ofcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylthiopyrimidin-4-ylethynyl)cyclohexan-1-ol](0.36 g, 0.82 mmol) in chloroform (5 mL) at -10° C. under an argonatmosphere was dropwise added over 20 min. a solution of3-chloroperoxybenzoic acid (0.34 g, 1.97 mmol) in chloroform (3 mL). Thereaction was stirred 3h at -10° C., then 3 h at room temperature. Asecond portion of 3-chloroperoxybenzoic acid (0.11 g, 0.62 mmol) inchloroform (1 mL) was added and stirring was continued for 1.5 h. Thereaction was quenched with sodium carbonate (5%), was extracted threetimes with dichloromethane, was dried (potassium carbonate) and wasevaporated. Purification by flash chromatography, eluting with 2.5:97.5methanol:dichloromethane, providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylsulfonylpyrimidin-4-ylethynyl)cyclohexan-1-ol]as a white foam (0.31 g, 81%), mp 75-77° C. ¹ H-NMR (400 MHz, CDCl₃) δ8.84 (d, J=5.3 Hz, 1 H), 7.54 (d, J=5.3 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 7.04 (dd, J=8.5, 2.3 Hz, 1 H), 6.85 (d, J=8.5 Hz, 1 H), 4.81 (m, 1H), 3.85 (s, 3 H), 3.73 (m, 1 H), 3.38 (s, 3 H), 2.20 (br d, J=12 Hz, 2H), 2.06 (m, 2 H), 1.8-2.0 (m, 10 H), 1.6 (m, 2 H) ppm.

19d)cis-[4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol]

Into a solution ofcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylsulfonylpyrimidin-4-ylethynyl)cyclohexan-1-ol](0.31 g, 0.66 mmol) in methanol (5 mL) at -78° C. was condensed liquidammonia (5 mL). The pressure tube was sealed and the reaction wasstirred at room temperature for 2 h. After cooling, the solvents wereevaporated. Purification by flash chromatography, eluting with 4:96methanol:dichloromethane, followed by trituration fromdichloromethane-ether-hexanes, providedcis-[4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-ol]as a white solid (0.19 g, 74%), mp 173-174° C. Anal. (C₂₄ H₂₉ N₃ O₃.0.25H₂ O) calcd: C, 69.96; H, 7.22; N, 10.20; found: C, 69.66; H, 7.10; N,10.11.

EXAMPLE 20cis-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol]

To a solution oftrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol](0.20 g, 0.64 mmol) and and 2-amino-5-bromopyrimidine (0.55 g, 3.2 mmol)in piperidine (2 mL) under an argon atmosphere were addedtetrakis(triphenyl-phosphine)palladium(0) (0.030 g, 4%), copper(I)iodide (0.006 g, 6%) and a small crystal of triphenylphosphine, and themixture was heated at 80-85° C. for 0.5 h. Water was added and themixture was extracted three times with dichloromethane, was dried(potassium carbonate) and was evaporated. Purification by two successiveflash chromatographies, eluting first with 5:95methanol:dichloromethane, then with 3:97 methanol:dichloromethane,providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-aminopyrimidin-5-ylethynyl)cyclohexan-1-ol]as a tan-brown solid (0.076 g, 29%), mp 136-137° C. Anal. (C₂₄ H₂₉ N₃O₃.0.75 H₂ O) calcd: C, 68.47; H, 7.30; N, 9.98; found: C, 68.25; H,7.09; N, 9.78.

EXAMPLE 21cis-[4-(thiazol-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol]

To a solution oftrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol](0.15 g, 0.48 mmol) and and 2-bromothiazole (0.20 mL, 2.4 mmol) intriethylamine (1.5 mL) under an argon atmosphere were addedtetrakis(triphenyl phosphine)palladium(0) (0.022 g, 4%), copper(I)iodide (0.006 g, 6%) and a small crystal of triphenylphosphine, and themixture was heated at 80-85° C. for 1 h. Ammonium chloride was added andthe mixture was extracted three times with dichloromethane, dried(magnesium sulfate), and evaporated. Purification by two successiveflash chromatographies, eluting first with 6:4 ethyl acetate:hexanes,then with 2:98 methanol:dichloromethane, providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-aminopyrimidin-5-ylethynyl)cyclohexan-1-ol]as an off-white foam (0.13 g, 68%), mp 45-48° C. Anal. (C₂₃ H₂₇ NO₃S.0.5 H₂ O) calcd: C, 67.95; H, 6.94; N, 3.45; found: C, 67.91; H, 6.76;N, 3.39.

EXAMPLE 22trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexyl-1-amine]

22a)cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexyl-1-amine]

To a solution oftrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol](1.0 g, 3.18 mmol), phthalimide (0.70 g, 4.77 mmol) andtriphenylphosphine (1.25 g, 4.77 mmol) in tetrahydrofuran (32 mL) wasdropwise added diethyl azodicarboxylate (0.75 mL, 4.77 mmol), and thesolution was stirred under an argon atmosphere at room temperature for 2h. Evaporation and purification by flash chromatography, eluting with2:8 ethyl acetate hexanes, provided the intermediate phthalirnide (1.43g) as a waxy white solid, mp 45-52° C. This was dissolved in 2:1ethanol:tetrahydrofuran (30 mL), was treated with hydrazine hydrate(1.55 mL, 32 mmol) and was stirred under an argon atmosphere at roomtemperature for 4 days. Water was added and the mixture was extractedthree times with 10:90 methanol:dichloromethane, was dried (potassiumcarbonate) and was evaporated. Purification by flash chromatography,eluting with 0.5:5:95 ammonium hydroxide:methanol:dichloromethane,providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexyl-1-amine]as a colorless oil (0.71 g, 72%). ¹ H-NMR (400 MHz, CDCl₃) δ 7.17 (d,J=2.2 Hz, 1H), 7.09 (dd, J=8.5, 2.2 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H),4.81 (m, 1H), 3.82 (s, 3 H), 3.26 (br s, 1H), 2.36 (s, 1H), 2.1-2.2 (m,4 H), 1.8-2.0 (m, 10 H), 1.6, (m, 2H) ppm.

22b)cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane]

A mixture ofcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexyl-1-amine](0.55 g, 1.75 mmol) and di-tert.-butyldicarbonate (0.42 g, 1.93 mmol) indichloromethane (8 mL) was stirred 20 h and was evaporated. Purificationby flash chromatography, eluting with 2:8 ethyl acetate:hexanesprovided, cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane]as a colorless oil (0.70 g, 97%). ¹ H-NMR (400 MHz, CDCl₃) δ 7.13 (d,J=2.2 Hz, 1H), 7.02(dd, J=8.5, 2.2 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.81(m, 1H), 4.64 (m, 1H), 3.84 (s, 3 H), 2.36 (s, 1H), 2.05 (m, 2 H),1.6-2.0 (m, 14 H), 1.45, (s, 9 H) ppm.

22c)trans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl-cyclohexane]

To a solution ofcis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexane](0.35 g, 0.85 mmol) and 2-bromopyridine (0.80 mL, 8.5 mmol) inpiperidine (2.5 mL) under an argon atmosphere were addedtetrakis(triphenylphosphine)palladium(0) (0.039 g, 4%), copper(I) iodide(0.010 g, 6%) and a small crystal of triphenylphosphine, and the mixturewas heated at 80-85° C. for 0.5 h in the dark. Water was added and themixture was extracted three times with dichloromethane, was dried(magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 25:75 ethyl acetate:hexanes ,providedtrans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl-cyclohexane]as a light yellow solid (0.30 g, 72%), mp 69-70° C. ¹ H-NMR (400 MHz,CDCl₃) δ 8.57 (d, J=4 Hz, 1 H), 7.66 (dt, J=8, 4 Hz, 1 H), 7.42 (d, J=8Hz, 1 H), 7.26 (br, 1 H), 7.17 (d, J=2.2 Hz, 1H), 7.09 (dd, J=8.5, 2.2Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.82 (m, 1H), 4.64 (br s, 1 H), 3.85(s, 3 H), 2.2 (m, 2H), 1.8-2.1 (m, 12 H), 1.6 (m, 2 H), 1.45, (s, 9 H)ppm.

22d)trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexyl-1-amine]

To a solution oftrans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynylcyclohexane](0.30 g, 0.61 mmol) in dichloromethane (5 mL) at 0° C. under an argonatmosphere was added trifluoroacetic acid (0.60 mL, 7.89 mmol). Thereaction was stirred at room temperature for 6 h, was cooled to 0° C.,quenched with sodium bicarbonate, was diluted with water, was extractedwith three times dichloromethane, was dried (magnesium sulfate) and wasevaporated. Purification by flash chromatography, eluting with 0.7:7:93ammonium hydroxide:methanol:dichloromethane providedtrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexyl-1-amine]as a very viscous oil (0.19 g, 82%). ¹ H-NMR (400 MHz, CDCl₃) δ 8.59 (d,J=4 Hz, 1 H), 7.63 (dt, J=7.8, 4 Hz, 1 H), 7.41 (d, J=7.8 Hz, 1 H), 7.26(m, 1 H), 7.22 (m, 2H), 6.81 (d, J=8.5 Hz, 1H), 4.84 (m, 1H), 3.81 (s, 3H), 3.4 (br s, 1 H), 2.31 (m, 4H), 1.8-2.0 (m, 10 H), 1.6 (m, 2 H) ppm.Anal. (C₂₅ H₃₀ N₂ O₂.0.5 H₂ O) calcd: C, 75.16; H, 7.82; N, 7.01; found:C, 75.42; H, 7.77; N, 6.91.

EXAMPLE 23trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexyl-1-formamide]

To a preparation of acetic formic anhydride (0.035 mL, 0.38 mmol) at 0°C. under an argon atmosphere was added a solution oftrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexyl-1-amine](0.096 g, 0.24 mmol) in tetrahydrofuran (1.5 mL). The mixture wasstirred for 3 h at room temperature, was diluted with dichloromethane,was washed with sodium bicarbonate and water, was dried (magnesiumsulfate) and was evaporated. Purification by flash chromatograhy,eluting with 5:95 methanol:dichloromethane, providedtrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexyl-1-formamide](which contains a trace of acetamide) as a white foam (0.08 g, 79%), mp75-76° C. Anal. (C₂₆ H₃₀ N₂ O₃.0.375 H₂ O) calcd: C, 73.43; H, 7.26; N,6.59; found: C, 73.46; H, 7.29; N, 6.25.

EXAMPLE 24trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine],cyclohexylsulfamate salt 24a)2-bromo-5-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene

2-Bromo-5-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene was prepared bystandard chemistry well known to those versed in the art and is a whitesolid, mp 48-49° C.

24b)trans-[1-tert-butoxycarbonylarnino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane]

To a solution ofcis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane](0.30 g, 0.73 mmol) and2-bromo-5-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene (0.18 g, 0.73 mmol)in triethylamine (5 mL) under an argon atmosphere were addedtetrakis(triphenylphosphine)palladium(0) (0.033 g, 4%) and copper(I)iodide (0.008 g, 6%) and a small crystal of triphenylphosphine, and themixture was heated at 80-85° C. for 1 h. Water was added and the mixturewas extracted three times with dichloromethane, was dried (magnesiumsulfate) and was evaporated. Purification by flash chromatography,eluting with 2:8 ethyl acetate:hexanes, followed by trituration fromdichloromethane-hexanes, providedtrans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane]as a yellow foam (0.38 g), containing ˜40% of1,4-bis-{[t-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexyl-1-amine]-4-yl}buta-1,3-diyneby ¹ H-NMR.

24c)trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine],cyclohexylsulfamate salt

A solution oftrans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane](0.38 g, containing 40% of the dimer) in dichloromethane (10 mL) at 0°C. under an argon atmosphere was treated with trifluoroacetic acid (0.50mL, 6.5 mmol) and the mixture was stirred for 24 h at room temperature.The solution was quenched with sodium bicarbonate at 0° C., was dilutedwith water, was extracted three times with 10:90methanol:dichloromethane, was dried (potassium carbonate) and wasevaporated. Purification by flash chromatogaphy, eluting with 0.5:5:95amnmonium hydroxide:methanol:dichloromethane, providedtrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine]as a glassy solid (0.18 g, 59%). This was dissolved in acetone (0.5 mL)and added to a solution of cyclohexylsulfamic acid (0.066 g, 0.37 mmol)in acetone (0.5 mL). The salt was isolated and the free amine wasrecovered. A second chromatography using the same solvent systemprovided free amine (0.048 g), which was treated with cyclohexylsulfamicacid (0.018 g, 0.10 mmol) in acetone (1 mL). After the addition of ether(20 mL), the precipitate was filtered off to providetrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine],cyclohexylsulfamate salt (0.043 g, 18%) as a white solid, mp 134-135° C.Anal. (C₃₃ H₄₄ N₄ O₆ S₂.0.5 H₂ O) calcd: C, 59.52; H, 6.81; N, 8.41;found: C, 59.37; H, 6.71; N, 8.46.

EXAMPLE 25cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexyl-1-amine]

25a)cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexane]

A solution of4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-1-one (0.82g,2.63 mmol), ammonium acetate (2.03 g, 26 mmol), sodium cyanoborohydride(0.17 g, 2.63 mmol) and several 4 Å molecular sieves in methanol (10 mL)was stirred under an argon atmosphere at room temperature for 3 days.Several crystals of methyl orange were added, then hydrogenchloride-saturated methanol to ˜pH 3. The reaction was made basic withsodium hydroxide (10%), was extracted with 10:90methanol:dichloromethane, was dried (potassium carbonate) and wasevaporated to provide crudetrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexyl-1-amine]as a yellow oil (0.88 g, 100%). A solution of the intermediate indichloromethane (15 mL) was treated with di-tert.-butyldicarbonate(0.63g, 2.89 mmol), was stirred 5 h and was evaporated. Purification byflash chromatography, eluting with 15: 85 ethyl acetate:hexanes,providedtrans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexane]as a white foam (0.57 g, 53%, ¹ H-NMR shows ˜20% cis isomer), mp. 39-43°C. ¹ H-NMR (400 MHz, CDCl₃) δ 7.11 (d, J=2.2 Hz, 1H), 7.04 (dd, J=8.5,2.2 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.80 (m, 1H), 4.6 (m, 0.2 H), 4.5(m, 0.8 H), 4.0 (m, 0.2 H), 3.84 (s, 0.6 H), 3.83 (s, 2.4 H), 2.43 (s,0.8 H), 2.36 (s, 0.2 H), 1.6-2.1 (m, 16 H), 1.46, (s, 9 H) ppm.

25b)cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynylcyclohexane

To a solution oftrans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane](0.45 g, 1.09 mmol) and 2-bromopyridine (1.0 mL, 11 mmol) in piperidine(3 mL) under an argon atmosphere were addedtetrakis(triphenylphosphine)palladium(0) (0.050 g, 4%), copper(I) iodide(0.012 g, 6%) and a small crystal of triphenylphosphine, and the mixturewas heated at 80-85° C. for 0.5 h in the dark. Water was added and themixture was extracted three times with dichloromethane, was dried(magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 2:8 ethyl acetate:hexanes, providedcis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynylcyclohexane]as a yellow foam (0.41 g, 78%, contains ˜35% trans isomer by ¹ H-NMR),mp 40-43° C. ¹ H-NMR (400 MHz, CDCl₃) δ 8.4 (m, 1 H), 7.65 (m, 1 H), 7.4(d, 1 H), 7.1 (m, 3 H), 6.85 (m, 1 H), 4.8 (m, 1H), 4.6 (m. 0.65 H),3.85 (s, 1 H), 3.84 (s, 2 H), 3.55 (m. 0.65 H), 1.5-2.2 (m, 16 H), 1.45,(s, 9H) ppm.

25c)cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexyl-1-amine]

To a solution ofcis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynylcyclohexane](0.41 g, 0.84 mmol) in dichloromethane (5 mL) at 0° C. under an argonatmosphere was added trifluoroacetic acid (0.65 mL, 8.4 mmol). Thereaction was stirred at room temperature for 20 h, was cooled to 0° C.,was quenched with sodium bicarbonate, was diluted with water, wasextracted twice with 10:90 methanol:dichloromethane, was dried(potassium carbonate) and was evaporated. Purification by flashchromatography, eluting with 0.5:5:95 ammoniumhydroxide:methanol:dichloromethane, followed by trituration from ether,providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexyl-1-amine]as a white solid (0.23 g, 69%, containing ˜20% of the trans isomer), mp78-80° C. Anal. (C₂₅ H₃₀ N₂ O₂) calcd: C, 66.06; H, 6.65; N, 6.16;found: C, 65.73; H, 6.96; N, 5.98.

EXAMPLE 26cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexyl-1-formamide]

To a preparation of acetic formic anhydride (0.057 mL, 0.64 mmol) at 0°C. under an argon atmosphere was added a solution ofcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexyl-1-amine](0.16 g, 0.40 mmol) in tetrahydrofuran (1.5 mL). The mixture was stirredfor 3 h at room temperature, was diluted with dichloromethane, waswashed with sodium bicarbonate and water, was dried (magnesium sulfate)and was evaporated. Purification by flash chromatograhy, eluting with5:95 methanol:dichloromethane, providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexyl-1-formamide](which contains a trace of acetamide) as a white foam (0.08 g, 79%), mp80-81° C. Anal. (C₂₆ H₃₀ N₂ O₃.0.375 H₂ O) calcd: C, 73.43; H, 7.26; N,6.59; found: C, 73.46; H, 7.29; N, 6.25.

EXAMPLE 29cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine],cyclohexylsulfamate salt

29a) 2-bromo-5-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene

2-Bromo-5-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene was prepared bystandard chemistry well known to those versed in the art and is a whitesolid, mp 48-49° C.

29b)cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane]

To a solution oftrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexyl-1-amine](0.21 g, 0.52 mmol) and2-bromo-5-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene (0.13 g, 0.52 mmol)in triethylamine (5 mL) under an argon atmosphere were addedtetrakis(triphenylphosphine)palladium(0) (0.024 g, 4%), copper(I) iodide(0.006 g, 6%) and a small crystal of triphenylphosphine, and the mixturewas heated at 80-85° C. for 1 h. Ammonium chloride was added and themixture was extracted three times with dichloromethane, was dried(magnesium sulfate) and was evaporated. Purification by two successiveflash chromatographies, eluting first with 2:8 ethyl acetate:hexanes,then with 2:8 acetone:hexanes, providedcis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane]as a white foam (0.20 g, 69%, contains ˜20% dimer impurity by ¹ H-NMR),mp 60-68° C.

29c)cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine],cyclohexylsulfarnate salt

A solution ofcis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane](0.21 g, containing 20% of the dimer) in dichloromethane (5 mL) at 0° C.under an argon atmosphere was treated with trifluoroacetic acid (0.28mL, 3.6 mmol) and was stirred 24 h at room temperature. The solution wasquenched with sodium bicarbonate at 0° C., was diluted with water, wasextracted three times with 10:90 methanol:dichloromethane, was dried(potassium carbonate) and was evaporated. Purification by flashchromatogaphy, eluting with 0.3:3:97 ammoniumhydroxide:methanol:dichloromethane, providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine]as a colorless glass (0.11 g, 0.24 mmol, 69%). This intermediate wasdissolved in acetone (0.5 mL) and was added to a solution ofcyclohexylsulfamic acid (0.045 g, 0.24 mmol) in acetone (1 mL). Afterthe addition of ether, the precipitate was filtered off to providecis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine],cyclohexylsulfamate salt (0.14 g, 58%) as a white solid, mp 152-154° C.Anal. (C₃₃ H₄₄ N₄ O₆ S₂) calcd: C, 60.34; H, 6.75; N, 8.53; found: C,60.01; H, 6.63; N, 8.32.

EXAMPLE 30cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-1-ol],

30a) 5-(3-iodophenyl)-3-methyl[1,2,4]oxadiazole

5-(3-Iodophenyl)-3-methyl[1,2,4]oxadiazole was prepared by standardchemistry well known to those versed in the art and is a white solid, mp102-103° C.

30b)cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-1-ol]

To a solution oftrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-1-ol](0.11 g, 0.35 mmol) and 5-(3-iodophenyl)-3-methyl[1,2,4]oxadiazole (0.15g, 0.52 mmol) in triethylamine (4 mL) under an argon atmosphere wereadded tetrakis(triphenylphosphine)palladium (0.017 g, 0.015 mmol),copper(I) iodide (0.004 g, 0.021 mmol) and a small crystal oftriphenylphosphine. After heating the mixture at 70° C. for 1.5 h., thereaction was quenched by addition of aqueous ammonium chloride solution,and the solvent was concentrated. The mixture was extracted three timeswith methylene chloride, and the organic phase was washed with water,was dried (sodium sulfate) and was evaporated. Purification by flashchromatography, eluting with 45:55 ethyl acetate:hexanes andcrystallizing from ethyl ether, providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-1-ol]as a white solid (0.144 g, 87%), mp 71.5-73.5° C. Anal. (C₂₉ H₃₂ N₂ O₄)calcd: C, 73.71; H, 6.83, N, 5.93 found: C, 73.60; H, 6.91, N, 5.76.

EXAMPLE 31cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-ol],

31a) 2-(3-iodophenyl)-5-methyl[1,3,4]oxadiazole

2-(3-Iodophenyl)-5-methyl[1,3,4]oxadiazole was prepared by standardchemistry well known to those versed in the art and is a white solid, mp112-113.5° C.

31b)cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-ol]

To a solution oftrans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol](0.125 g, 0.40 mmol) and 2-(3-iodophenyl)-5-methyl[1,3,4]oxadiazole(0.171 g, 0.60 mmol) in triethylamine (7 mL) under an argon atmospherewere added tetrakis(triphenylphosphine)palladium (0.020 g, 0.017 mmol),copper(I) iodide (0.0042 g, 0.022 mmol) and a small crystal oftriphenylphosphine. After heating the mixture at 75° C. for 1.75 h, thereaction was quenched by addition of aqueous ammonium chloride solution,and the solvent was concentrated. The mixture was extracted three timeswith methylene chloride, and the organic phase was washed with water,was dried (sodium sulfate) and was evaporated. Purification by flashchromatography, eluting with 40 to 50% ethyl acetate in methylenechloride and crystallizing from ethyl ether, providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-ol]as a white solid (0.119 g, 63%), mp 117.5-119° C. Anal. (C₂₉ H₃₂ N₂O₄.1/8H₂ O) calcd: C, 73.36; H, 6.85, N, 5.90 found: C, 73.25; H, 6.94,N, 5.75. ¹ H-NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.98 (d-d, J=1.4 Hz;J=7.9 Hz, 1H), 7.60 (d-d, J=1.3 Hz, J=7.8 Hz, 1H), 7.46 (t, J=7.8 Hz,1H), 7.19 (d, J=2.2, 1H), 7.10 (d-d, J=2.1 Hz, J=8.5 Hz, 1H), 6.85 (d,J=8.5 Hz, 1H), 4.81 (p, J=4.3 Hz, 1H), 3.85 (s, 3H), 3.73 (m, 1H), 2.63(s, 3H), 2.2-1.8 (m, 14H), 1.7-1.5 (m, 7H with H₂ O).

EXAMPLE 32cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-ol],

To a solution of4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-one(0.084 g, 0.18 mmol, prepared as described in co-pending applicationP50283 filed on even date herewith) in 1,2-dimethoxyethane (3 mL) underan argon atmosphere was added dropwise a solution of sodium borohydride(0.015 g, 0.40 mmol) in 1,2-dimethoxyethane (5 mL). After 2 h stirringat room temperature, the reaction was quenched by addition of aqueousammonium chloride solution. The solvent was concentrated and the residuewas extracted into methylene chloride, was washed with water, was dried(sodium sulfate) and was evaporated. Purification by flashchromatography, eluting with 35% ethyl acetate in hexanes andcrystallizing from ethyl ether, providedcis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-ol]as a white solid (0.050 g, 58%), mp 101-103° C. Anal. (C₂₉ H₃₂ N₂O₄.1/5H₂ O) calcd: C, 73.15; H, 6.86, N, 5.88 found: C, 73.11; H, 6.85,N, 5.85. ¹ H-NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 8.00 (d, J=7.9 Hz,1H), 7.58 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.19 (d, J=2.2,1H), 7.10 (d-d, J=2.1 Hz, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.82(p, J=4.3 Hz, 1H), 3.85 (s, 3H), 3.72 (m, 1H), 2.67 (s, 3H), 2.2-1.8 (m,13H), 1.7-1.5 (m, 6H with H₂ O).

The other compounds of this invention may be prepared by proceeding in asirnilar manner, but substituting the appropriate starting materials andintermediates for those recited in this Example. Examples are:

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-trifluoromethyl[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-ol],

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-trifluoromethyl[1,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-1-ol],

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-trifluoromethyl[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-ol],and

cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-trifluoromethyl[1,3,4]thiadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-ol].

UTILITY EXAMPLES EXAMPLE A Inhibitory Effect of Compounds of Formula (I)on in vitro TNF Production by Human Monocytes

The inhibitory effect of compounds of Formula (I) on in vitro TNFproduction by human monocytes may be determined by the protocol asdescribed in Badger et al., EPO published Application 0 411 754 A2, Feb.6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

EXAMPLE B

Two models of endotoxic shock have been utilized to determine in vivoTNF activity for the compounds of Formula (I). The protocol used inthese models is described in Badger et al., EPO published Application 0411 754 A2, Feb. 6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

The compound of Example 1 herein demonstrated a positive in vivoresponse in reducing serum levels of TNF induced by the injection ofendotoxin.

EXAMPLE C Isolation of PDE Isozymes

The phosphodiesterase inhibitory activity and selectivity of thecompounds of Formula (I) can be determined using a battery of fivedistinct PDE isozymes. The tissues used as sources of the differentisozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE Ic, guinea-pigheart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5)PDE V (also called "Ia"), canine trachealis. PDEs Ia, Ib, Ic and III arepartially purified using standard chromatographic techniques [Torphy andCieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purified tokinetic homogeneity by the sequential use of anion-exchange followed byheparin-Sepharose chromatography [Torphy et al., J. Biol. Chem.,267:1798-1804, 1992].

Phosphodiesterase activity is assayed as described in the protocol ofTorphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive IC₅₀'s in the nanomolar to μM range for compounds of the workings examplesdescribed herein for Formula (I) have been demonstrated.

What is claimed is:
 1. A compound of Formula I ##STR6## wherein: R₁ is--(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) C(O)NR₄ (CR₄ R₅)_(m)R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆, or --(CR₄ R₅)_(r) R₆ wherein thealkyl moieties unsubstituted or substituted with one or more halogens;mis 0 to 2; n is 1 to 4; r is 0 to 6; R₄ and R₅ are independentlyselected hydrogen or C₁₋₂ alkyl; R₆ is hydrogen, methyl, hydroxyl, aryl,halo substituted aryl, aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃alkyl, indanyl, indenyl, C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl,furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl,tetrahydrothiopyranyl, thiopyranyl, C₃₋₆ cycloalkyl, or a C₄₋₆cycloalkyl containing one or two unsaturated bonds, wherein thecycloalkyl or heterocyclic moiety is unsubstituted or substituted by 1to 3 methyl groups, one ethyl group, or an hydroxyl group; providedthat:a) when R₆ is hydroxyl, then m is 2; or b) when R₆ is hydroxyl,then r is 2 to 6; or c) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then m is 1 or 2; or d) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then r is 1 to 6; e) when n is 1 and m is 0, then R₆ is other than H in--(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆ ; X is YR₂, fluorine, NR₄ R₅, or formylamine; Y is O or S(O)_(m') ; m' is 0, 1, or 2; X₂ is O or NR₈ ; X₃ ishydrogen or X; X₄ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈ R₈, or NR₈R₈ ; R₂ is independently selected from --CH₃ or --CH₂ CH₃ optionallysubstituted by 1 or more halogens; s is 0 to 4; W is alkyl of 2 to 6carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbonatoms; R₃ is COOR₁₄, C(O)NR₄ R₁₄ or R₇ ; Z is OR₁₄, OR₁₅, SR₁₄,S(O)_(m') R₇, S(O)₂ NR₁₀ R₁₄, NR₁₀ R₁₄, NR₁₄ C(O)R₉, NR₁₀ C(Y')R₁₄, NR₁₀C(O)OR₇, NR₁₀ C(Y')NR₁₀ R₁₄, NR₁₀ S(O)₂ NR₁₀ R₁₄, NR₁₀ C(NCN)NR₁₀ R₁₄,NR₁₀ S(O)₂ R₇, NR₁₀ C(CR₄ NO₂)NR₁₀ R₁₄, NR₁₀ C(NCN)SR₉, NR₁₀ C(CR₄NO₂)SR₉, NR₁₀ C(NR₁₀)NR₁₀ R₁₄, NR₁₀ C(O)C(O)NR₁₀ R₁₄, or NR₁₀C(O)C(O)OR₁₄ ; Y' is O or S; R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkylwherein the R₁₂ or C₁₋₆ alkyl group is unsubstituted or substituted oneor more times by methyl or ethyl unsubstituted or substituted by 1-3fluorines, --Br, --Cl, --NO₂, --NR₁₀ R₁₁, --C(O)R₈, --CO₂ R₈,--O(CH₂)_(q) R₈, --CN, --C(O)NR₁₀ R₁₁, --O(CH₂)_(q) C(O)NR₁₀ R₁₁,--O(CH₂)_(q) C(O)R₉, --NR₁₀ C(O)NR₁₀ R₁₁, --NR₁₀ C(O)R₁₁, --NR₁₀C(O)OR₉, --NR₁₀ C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀ R₁₁,--C(NCN)SR₉, --NR₁₀ C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁, --NR₁₀ S(O)₂ R₉,--S(O)_(m') R₉, --NR₁₀ C(O)C(O)NR₁₀ R₁₁, --NR₁₀ C(O)C(O)R₁₀, or R₁₃ ; qis 0, 1, or 2; R₁₂ is R₁₃, (CH₂)_(q), C₃ -C₇ cycloalkyl, (2-, 3- or4-pyridyl), pyrimidyl, pyrazolyl, (1-or 2-imidazolyl), pyrrolyl,piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl),quinolinyl, naphthyl, or phenyl; R₈ is independently selected fromhydrogen or R₉ ; R₉ is C₁₋₄ alkyl optionally substituted by one to threefluorines; R₁₀ is OR₈ or R₁₁ ; R₁₁ is hydrogen, or C₁₋₄ alkylunsubstituted or substituted by one to three fluorines; or when R₁₀ andR₁₁ are as NR₁₀ R₁₁ they may together with the nitrogen form a 5 to 7membered ring comprised of carbon or carbon and one or more additionalheteroatoms selected from O, N, or S; R₁₃ is oxazolidinyl, oxazolyl,thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl,thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each ofthese heterocyclic rings is connected through a carbon atom and each maybe unsubstituted or substituted by one or two C₁₋₂ alkyl groups; R₁₄ ishydrogen or R₇ ; or when R₈ and R₁₄ are as NR₈ R₁₄ they may togetherwith the nitrogen form a 5 to 7 membered ring comprised of carbon orcarbon and one or more additional heteroatoms selected from O, N, or S;provided that:(f) R₇ is not C₁₋₄ alkyl unsubstituted or substituted byone to three fluorines;or the pharmaceutically acceptable salts thereof.2. A compound according to claim 1 wherein R₁ is --CH₂ -cyclopropyl,cyclopentyl, 3-hydroxycyclopentyl, methyl or CF₂ H; X is YR₂ ; Y isoxygen; X₂ is oxygen; X₃ is hydrogen; and R₂ is CF₂ H or methyl, W isacetylene or 1,3-butadiynyl, and R₃ is C(O)OR₁₄, or R₇.
 3. A compoundwhichiscis-[4-[(2-aminopyrimidin-5-yl)ethynyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-ol]or,cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-ol].4. A pharmaceutical composition comprising a compound of Formula Iaccording to claim 1 and a pharmaceutically acceptable excipient.
 5. Amethod for treating asthma which comprises administering to a mammal inneed thereof a compound of formula (I) according to claim 1 alone oradmixed with a pharmaceutically acceptable excipient.